#3566 ACSS2 AGGRAVATES RENAL TUBULAR INFLAMMATION BY INDUCING THE DYSREGULATION OF FATTY ACID METABOLISM AND MITOCHONDRIAL OXIDATIVE STRESS IN DIABETIC MICE

Abstract Background and Aims Treatment options for diabetic nephropathy (DN) are currently limited. Chronic renal inflammation has been widely recognized as a major promoter of DN. The tubular epithelial cells source IL-1β in db/db mice. Inhibition Acetyl CoA Synthase 2 (ACSS2) shown to promote high-fat diet-induced liver injuries, but the underlying mechanism action ACSS2 injuries not elucidated. Method Streptozotocin (STZ) was intraperitoneally injected establish mouse model. We investigated effects on diabetes-induced injury transgenic mice with global acss2 knockout (acss2−/−). PAS staining carried out evaluate pathological kidneys tissue immunostaining conducted detect expression macrophage distribution kidney tissues HK-2 cell culture model achieved by high glucose stimulation vitro. Real-time PCR analysis applied gene inflammatory factors IL-1β, TNF-α, MCP-1. Western Blot immunofluorescence were activation NLRP3 pathway mitochondrial reactive oxygen species (ROS). Results upregulated STZ-induced cells, which is significantly co-expressed IL-1β-positive acss2−/- exhibited decreased inhibited NOD-like receptor protein 3 (NLRP3) inflammasome evidenced elevated levels cleaved caspase-1 when compared wild-type selective inhibition protected vitro exposed environment downregulating ameliorating oxidative stress. Mechanistically, we showed that dysfunction preceded response elimination ROS using mitochondria-targeted antioxidants (mito-TEMPO) reversed HG-mediated recapitalized phenotype observed acss2-/- also found cytoplasm ACSS2, increased after HG stimulation, induced fatty acid synthase (FASN) mediated overproduction free acid. Downregulating FASN FASN-small interfering RNA restored function, suppressed activation. Conclusion In conclusion, upregulation led subsequent FASN-mediated dysregulation metabolism overproduction, eventually causing inflammation. Therefore, our findings established role epithelium unveiled its action. appears promising target treating